Hydroxy-substituted antifungals

- Schering Corporation

A compound represented by the formula I ##STR1## wherein X is independently both F or both Cl or one X is independently F and the other is independently Cl; R.sub.1 is a straight or branched chain (C.sub.3 to C.sub.8) alkyl group substituted by one or two hydroxy moieties, an ether or ester thereof (e.g., a polyether ester, heterocyclic ester amino acid ester or phosphate ester) thereof and the carbon with the asterisk (*) has the R or S absolute configuration or a pharmaceutically acceptable salt thereof and pharmaceutical compositions thereof useful for treating and/or preventing fungal infections are disclosed.

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Claims

1. A compound represented by the formula I ##STR61## wherein X is independently both F or both Cl or one X is independently F and the other is independently Cl;

R.sub.1 is a straight or branched chain (C.sub.3 to C.sub.8) alkyl group substituted by one or two hydroxy moieties; and esters and ethers thereof

2. A compound of claim 1 wherein R.sub.1 is a straight or branched chain (C.sub.4 -C.sub.5) alkyl group substituted by at least one hydroxy moiety.

3. A compound of claim 1 wherein R.sub.1 is CHR.sub.2 R.sub.3 and which is represented by the formula II ##STR62## wherein X is independently both F or both Cl or one X is independently F and the other is independently Cl;

R.sub.2 is H or (C.sub.1 -C.sub.3) alkyl and R.sub.3 is (C.sub.1 -C.sub.3) alkyl substituted by one hydroxy moiety and the carbons with the asterisks (*) have the R or S absolute configuration;

4. A compound of claim 1 wherein R.sub.1 is CHR.sub.2 R.sub.3 and which is represented by the formula IIa ##STR63## wherein X is independently both F or both Cl or one X is independently F and the other is independently Cl;

R.sub.2 is H or (C.sub.1 -C.sub.3) alkyl and R.sub.3 is (C.sub.1 -C.sub.3) alkyl substituted by one hydroxy moiety and the carbon with the asterisk (*) has the R or S absolute configuration;

5. A compound of claim 3 wherein R.sub.2 or R.sub.3 is (C.sub.1 -C.sub.2)alkyl and each X is F.

6. A compound of claim 1 wherein R.sub.1 is a hydroxy-substituted C.sub.4 - or C.sub.5 -alkyl group selected from:

--CH(C.sub.2 H.sub.5)CH(R.sub.4)CH.sub.3, --CH(C.sub.2 H.sub.5)CH.sub.2 CH.sub.2 R.sub.4, --(CH.sub.2).sub.2 --CH(R.sub.4)C.sub.2 H.sub.5, --CH(CH.sub.3)CH(R.sub.4)CH.sub.3, --CH(C.sub.2 H.sub.5)CH.sub.2 R.sub.4 and --CH(CH.sub.3)CH.sub.2 CH.sub.2 R.sub.4
R.sub.4 is OH or an ester thereof and the carbons with the asterisk(*) have the R or S absolute configuration or a pharmaceutically acceptable salt thereof.

7. A compound represented by formula III ##STR64## wherein R.sub.5 is ##STR65## or an ester thereof or a pharmaceutically acceptable salt thereof.

8. A compound represented by the formula IV ##STR66## wherein R.sub.9 =--CH(C.sub.2 H.sub.5)CH(R.sub.6)CH.sub.3 or --CH(CH.sub.3)CH(R.sub.6)CH.sub.3

R.sub.6 =is OH, and the carbons with the asterisks (*) have the R or S absolute configuration; or an ester or ether thereof or a pharmaceutically acceptable salt thereof.

9. A compound represented by the formula IVa ##STR67## wherein R.sub.9 =--CH(C.sub.2 H.sub.5)CH(R.sub.6)CH.sub.3 or --CH(CH.sub.3)CH(R.sub.6)CH.sub.3

R.sub.6 is OH, and the carbon with the asterisk (*) has the R or S absolute configuration; or an ester thereof or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition for treating or preventing fungal infection comprising an antifungally effective amount of a compound of claim 1 together with a pharmaceutically acceptable carrier therefor.

11. A method of treating and/or preventing fungal infections in a mammal afflicted with same which comprises administering an antifungally effective amount of a compound of claim 1 sufficient for such treating or preventing.

12. The pharmaceutical composition of claim 10 wherein the mode of administration is oral or parenteral.

13. The compound of claim 1 wherein the ester is a polyether ester.

14. The compound of claim 7 wherein the ester is a polyether ester.

15. The compound of claim 1 wherein the ester is an amino acid ester.

16. The compound of claim 7 wherein the ester is an amino acid ester.

17. The compound of claim 7 wherein the amino acid ester is derived from reaction of glycine and a compound of formula III.

18. The compound of claim 1 wherein the ester is a phosphate ester.

19. The compound of claim 7 wherein the ester is a phosphate ester.

Referenced Cited
U.S. Patent Documents
4791111 December 13, 1988 Heeres et al.
5023258 June 11, 1991 Gymer et al.
5039676 August 13, 1991 Saksena et al.
Foreign Patent Documents
0 539 938 A1 May 1993 EPX
WO 89/04829 June 1989 WOX
WO 95/17407 June 1995 WOX
WO 95/19983 July 1995 WOX
Patent History
Patent number: 5698557
Type: Grant
Filed: Jun 17, 1996
Date of Patent: Dec 16, 1997
Assignee: Schering Corporation (Kenilworth, NJ)
Inventors: Anil K. Saksena (Upper Montclair, NJ), Viyyoor M. Girijavallabhan (Parsippany, NJ), Raymond G. Lovey (West Caldwell, NJ), Russell E. Pike (Stanhope, NJ)
Primary Examiner: Matthew V. Grumbling
Assistant Examiner: Brenda Coleman
Attorney: Thomas D. Hoffman
Application Number: 8/664,758
Classifications
Current U.S. Class: 514/252; Five-membered Hetero Ring Having Two Or More Ring Hetero Atoms Of Which At Least One Is Nitrogen (544/366)
International Classification: A61K 31495; C07D40300;